DESCRIPTION: The cardiovascular (CV) system is a common site of spontaneous as well as pharmacologically-induced birth defects that are associated with high morbidity and mortality. Nevertheless, a rat, fetal alcohol exposure (FAE) model that recapitulates some of the FAS CV-defects found in man has not been firmly established. This is our immediate and primary goal. Our preliminary data suggest that several biochemical and molecular indices of heart development are altered in ventricles from FAE male and female offspring. Based on these data, AND information available from the literature, we hypothesize that in utero FAE will modify heart development by mechanisms that remain to be fully elucidated. Because cardiomyocyte proliferation occurs almost exclusively during embryonic and fetal heart development, we postulate that FAE will reduce the total myocyte cell number in the ventricle. For this postulate to be critically tested, we must establish the rat FAE model. To do this, we will focus on ethanol's effects upon in utero cardiomyocyte development and ventricular formation with a potential impact upon structure-function relationships. FAE exposure during near full-term rat gestation (Days 7-to-Term) will be the dietary paradigm used to establish that FAE negatively influences: 1) the cardiomyocyte lineage's highly regulated proliferative expansion OR 2) effects cardiomyocyte population expansion and concomitant differentiation. We anticipate FAE-induced deficits in final ven-tricular myocyte cell number of 5-20%. Such deficits would blunt myocyte-influenced postnatal capillary angiogenesis and ventricular remodeling with structure-function, pathophysiologic consequences. To establish the rat FAE exposure conditions that induces developmental heart defects, pregnant dams will ingest liquid diets containing ethanol (6.5% vol/ vol; approximately 100 mg/dl blood alcohol) to provide 35% of their total caloric intake for the indicated period. At gestational days 17 and 20, AND postnatal days 1, 4, 7, and 14, ventricles from control, Pair Fed and FAE animals will be examined according to this aim: Specific aim #1 will Establish the Rat Model wherein near full-term FAE reproducibly blunts anatomical, biochemical, molecular and/or flow cytometric indices of cardiomyocyte proliferation and/or differentiation AND, overall heart growth/morphogenesis in the late fetal-to-neonatal animal, independent of any underlying gender- or nutritional-based influences. The proposed studies are required to establish the rat as an obliging animal model of human FAE-induced alterations in the CV system, with an emphasis upon the heart. The experimental design will test AND resulting data clarify the validity of our postulate that FAE-induced heart developmental defects that are manifest by reduced myocyte proliferation and/or differentiation, with potential underlying gender influences. Mechanistic insights into FAE-induced alterations may be ascertained from the results of our proposal AND they will be used to direct future cause-and-effect studies.